Compositions and methods for the topical administration of spironolactone for the treatment of cutaneous signs of excess androgen and chronic stress response

ABSTRACT

The present disclosure provides methods for treating or alleviating symptoms of a disease, disorder, or condition related to excess androgen or stress-induced skin changes in a subject in need thereof by topically administering a pharmaceutical composition comprising a pharmaceutically effective amount of spironolactone to the subject. Other aspects relate to methods for providing anti-oxidative stress, anti-inflammatory and anti-aging benefits for the skin to a subject in need thereof by topically administering a pharmaceutical composition comprising a pharmaceutically effective amount of spironolactone to the subject. Surprisingly, it has been found that spironolactone may be topically administered with reduced adverse effect compared to systemic administration of the same medication.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/931,828, filed Jul. 17, 2020, entitled “COMPOSITIONS ANDMETHODS FOR THE TOPICAL ADMINISTRATION OF SPIRONOLACTONE FOR THETREATMENT OF CUTANEOUS SIGNS OF EXCESS ANDROGEN AND CHRONIC STRESSRESPONSE,” the content of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present invention relates to compositions comprising spironolactoneand methods of using the same.

BACKGROUND OF THE INVENTION

Spironolactone is known for various medical applications and indicationsas an orally administered medication. For instance, high doses of oralspironolactone have been used in the treatment of acne vulgaris as wellas hirsutism (Shaw, J. C., J. Am. Acad. Dermat. 24:236-243, 1991).Unfortunately, the systemic administration of spironolactone hasresulted in a number of adverse effects, including irregularmenstruation, arrest and/or reversal of the development of secondarysexual characteristics, total volume depletion due to diuresis, nausea,dizziness, etc.

More recently, topically administered spironolactone has beeninvestigated for use in the treatment of acne vulgaris. However, resultsfrom these studies have been limited and conflicting in terms ofoutcome.

As such, there remains a need for improved compositions and methods fortopically administering spironolactone.

SUMMARY OF THE INVENTION

The present disclosure provides compositions and methods for topicallyadministering spironolactone to a subject in need thereof, wherein thecompositions and methods result in reduced adverse effects, as comparedto systemic administration.

In certain embodiments, the compositions and methods are for thetreatment or alleviation of the signs and symptoms of diseases,disorders, or conditions related to excess androgen in both men andwomen. By way of example, the disease, disorder, or condition ofinterest may be selected from those patients receiving sex hormonereplacement, including but not limited to patients with polycysticovarian syndrome (PCOS), metabolic syndromes, congenital adrenalhyperplasia, patients undergoing gender reassignment, or those receivingsex hormone due to total orchiectomy after testicular cancer or gonadalfailure. In other embodiments, the disease, disorder, or condition ofinterest may include those wherein excess androgen produces undesirablecutaneous outcomes in patients, including unwanted hair growth, acneeruptions, and premature senescence of the skin, which presents in amyriad of ways including but not limited to hyper and hypopigmentation,atrophy and laxity, and rhytids.

In other embodiments, the present disclosure provides methods for thetreatment or alleviation of symptoms of a disease, disorder, orcondition related to excess androgen, the method comprising topicallyadministering a pharmaceutical composition comprising an effectiveamount of spironolactone to a subject in need thereof. In certainembodiments, the pharmaceutical composition comprises from about 5% toabout 25% spironolactone by weight of the total composition.

DETAILED DESCRIPTION OF THE INVENTION

As discussed in further detail herein, the present disclosure providescompositions and methods for topically administering spironolactone to asubject in need thereof, wherein the compositions and methods result inreduced adverse effects. In certain aspects, the compositions andmethods are useful in treating skin diseases in special patientpopulations with reduced adverse effects, for the purpose of achievingthe desired clinical outcomes while maximizing subject safety.

Surprisingly, it has been found that spironolactone may be topicallyadministered to provide for the treatment or alleviation of signs andsymptoms of a disease, disorder, or condition related to excess androgenor stress-induced skin changes in a subject in need thereof, withreduced adverse effect compared to systemic administration.

The section headings are used herein for organizational purposes onlyand not to be construed as in any way limiting the subject matterdescribed.

Definitions

As used herein, excess androgen refers to an endocrinologic stateassociated with levels of androgens beyond those deemed to be clinicallynormal or effective, typically producing unwanted outcomes. This canaffect people of any age and gender, with a predilection for youngerfemales. In certain aspects, the disclosure includes cutaneous signs ofexcess androgen production, which may manifest as inflammatory papules,pustules, comedones, nodules, cysts, excess hair or inappropriate hairproduction (hirsutism), premature hair loss (alopecia), redness(erythema), and excessive oil secretion with or without superimposedfungal/yeast infection (seborrhea). In accordance with the disclosure,diseases, disorders and conditions causing excess androgen include, butare not limited to:

sex hormone replacement, PCOS, metabolic syndrome, congenital adrenalhyperplasia and other inborn errors of steroidogenesis and metabolism,pituitary, thyroid, or gonadal diseases, puberty syndromes, andiatrogenic Cushingoid syndromes seen in patients regularly receivingcorticosteroids.

In the context of the present disclosure, “spironolactone” has thefollowing chemical structure:

As recognized by those of skill in the art, spironolactone may also bereferred to as, SC-9420; NSC-150339; 7α-acetylthiospirolactone; and7α-acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone.

As used herein, the term “pharmaceutically acceptable excipient” refersto an excipient for administration of a pharmaceutical agent, andincludes any and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, gels, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art. The term refers to any pharmaceuticalexcipient that may be administered without undue toxicity.Pharmaceutically acceptable excipients are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there exists awide variety of suitable formulations of pharmaceutical compositions ofthe present invention (see, e.g., Remington's Pharmaceutical Sciences).

Methods of Topical Administration

The present disclosure provides methods for topically administering apharmaceutical composition comprising a pharmaceutically effectiveamount of spironolactone to a subject in need thereof, wherein themethods result in reduced adverse effects compared to systemicadministration. Surprisingly, it has been found that spironolactone maybe topically administered to provide for the treatment or alleviation ofsymptoms of a disease, disorder, or condition related to excess androgenin a subject in need thereof, with reduced adverse effect compared tosystemic administration of the same medication.

In certain embodiments, the methods are for the treatment or alleviationof symptoms of a disease, disorder, or condition related to excessandrogen. By way of example, the disease, disorder, or condition relatedto excess androgen may be selected from patients receiving sex hormonereplacement, PCOS, metabolic syndrome, congenital adrenal hyperplasia,or seborrheic dermatitis.

In other embodiments, the present disclosure provides methods for thetreatment or alleviation of symptoms of a disease, disorder, orcondition related to excess androgen, the method comprising topicallyadministering a pharmaceutical composition comprising an effectiveamount of spironolactone to a subject in need thereof. In certainembodiments, the pharmaceutical composition comprises from about 5% toabout 25% spironolactone by weight of the total composition, about 5.1%to about 25% spironolactone by weight of the total composition, about7.5% to about 25% spironolactone by weight of the total composition,about 10% to about 25% spironolactone by weight of the totalcomposition, etc.

Without intending to be limited by theory, in accordance with aspects ofthe disclosure, spironolactone may exert its biological effects in thetreatment and alleviation of symptoms of diseases, disorders, orconditions related to excess androgen via action on the pilosebaceousunit, which includes the entire structure of the hair follicle and itsassociated glands.

In certain aspects, the effective topical administration ofspironolactone may affect the microflora of the pilosebaceous unit.Without intending to be limited by theory, a reduction in the productionof sebum from the sebocytes (those cells in the skin which have multiplehormone receptors) will potentially prevent the growth of pathogenicmicroflora, including yeasts, bacteria, and other micro-organismsthought to feed on sebum, such as Demodex mites.

In particular, certain embodiments of the disclosure relate to thetreatment of conditions involving the skin microflora of the genusMalassezia, such as seborrheic dermatitis and different forms ofrosacea. Malassezia (former name Pityrosporum) is a normal yeast foundon human skin, but in some individuals this microflora causes pathologicskin findings, including but not limited to acneiform eruptions,pityrosporum folliculitis, generalized pruritus in the elderly andchildren, exacerbated atopic dermatitis of the head and neck inadolescents and adults, and cradle cap in infants.

Seborrheic dermatitis is a ubiquitous, chronic, inflammatory skincondition affecting any age group and is associated with highpsychological morbidity. Furthermore, seborrheic dermatitisdisproportionately affects subjects under high psychological stress, aswell as subjects with neurodegenerative diseases such as multiplesclerosis, Parkinson's disease, and subjects who have had spinal cordinjuries or strokes, and subjects with HIV-AIDS regardless of treatmentstatus.

In another aspect, topical spironolactone may provide anti-oxidativestress, anti-inflammatory and anti-aging benefits for the skin. Unlikeprevious anti-androgen drugs used to treat acne vulgaris, which did notpossess any anti-mineralocorticoid or anti-glucocorticoid effects, inaccordance with aspects of the disclosure, topical spironolactoneexhibits anti-oxidative, anti-inflammatory and anti-aging effects.Without intending to be limited by theory, topical spironolactone isbelieved to achieve such anti-oxidative, anti-inflammatory andanti-aging benefits by virtue of its ability to act on not only theandrogen receptors, but also the glucocorticoid and mineralocorticoidreceptors.

Aldosterone is a mineralocorticoid hormone produced by the adrenalglands. It primarily acts on the sodium channels of the renal tubules toincrease water and ion absorption, thus resulting in an increase inblood pressure that in turn provides an important mechanism for thecardiovascular system to respond to physiologic stress. As such, itsactivity has major effects on the vasculature, heart, and kidneys.Aldosterone has been implicated in oxidative stress, chronicinflammation, and scarring (fibrosis) of the heart, kidneys, andvascular system (Brown, N. J. Curr Opin Nephrol Hypertens.14(3):235-41). By competing for the same biding site on themineralocorticoid receptors in the renal tubules, spironolactoneinhibits the actions and thus downstream effects of aldosterone on itstargets.

In accordance with certain aspects of the disclosure, topicalspironolactone exerts activity on the structures of the skin, which alsosuffer chronic damage from systemic stress and inflammation. Withoutintending to be limited by theory, the influence of hormones andpro-inflammatory chemokines is implicated, as sebaceous glands areminiature neuroendocrine organs embedded within the skin. As such, incertain aspects of the disclosure, topical use of spironolactone mayeffectively reduce oxidative stress and end-organ damage of the skin viaits actions on the androgen, glucocorticoid, and mineralocorticoidreceptors. In other words, topical use of spironolactone hasanti-oxidative-stress and anti-aging benefits for the skin, whilesparing its systemic effects on unintended organs, thus allowing forfewer to no adverse effects.

As mentioned above, spironolactone has affinity for the glucocorticoidreceptor (anti-inflammatory), the androgen receptor (anti-androgen), andthe mineralocorticoid receptor (anti-stress). Its real-world use couldbenefit several skin conditions in the general population as well as insub-populations of patients undergoing high oxidative stress, includingbut not limited to those receiving systemic chemotherapies, humansexposed to increased amounts of UV radiation, air pollution, and evenchronic psychological stress states, such as those experiencingpost-traumatic stress disorder.

In its topical form, spironolactone may be used as a preventative agentto maintain youthful skin thickness, color, and texture. As such, incertain aspects the composition and methods provide an anti-agingtopical agent comprising spironolactone, optionally to be used inconcert with other well-known preventative topical products, such assunscreens.

While it would certainly not address the known stressor for the patient,nor the psychiatric comorbidity, the use of topical spironolactone mayprevent long lasting physical changes in the skin, which in turn cancause long-term psycho-social morbidity such as shame, body dysmorphia,and the ability to maintain gainful employment if the patient isstigmatized by skin disease. In certain aspects, the compositions andmethods of the disclosure may be used in concert with other psychiatricand psychological modalities, as well as to prevent skin changes andpossibly the comorbid psychiatric conditions as patients undergo extremephysical stressors such as cancer treatments.

In other embodiments, the subjects to be treated may have geneticallyinfluenced cutaneous milieus, which makes them susceptible to theeffects of excess androgen and increased stress. Without intending to belimited by theory, these genetic factors alone or in combination withlifestyle and environmental stresses may trigger immune and inflammatorychemical cascades as well as interactions between the immune system andthe pilosebaceous microflora to develop skin manifestations anddiseases, such as acne vulgaris, hirsutism, alopecia, seborrheicdermatitis, premature photoaging, etc.

As will be recognized by those of skill in the art, the effects on thepilosebaceous unit including the sebaceous glands are generally dosedependent. In accordance with aspects of the disclosure, the topicaladministration of spironolactone, even when administered at higherconcentrations in the topical compositions, (e.g., about 5% to about 25%by weight of the total composition, about 5.1% to about 25%spironolactone by weight of the total composition, about 7.5% to about25% spironolactone by weight of the total composition, about 10% toabout 25% spironolactone by weight of the total composition, etc.),result in reduced adverse events, as compared to systemicadministration.

Pharmaceutical Compositions

The pharmaceutical compositions of the present disclosure generallycomprise an effective amount of spironolactone and at least onepharmaceutically acceptable excipient. In certain embodiments, thespironolactone may be in any known form, including tautomers,geometrical isomers, optically active forms, enantiomeric mixturesthereof, pharmaceutically acceptable salts and pharmaceutically activederivatives and metabolites thereof.

Metabolites of spironolactone including 7-α-thiospironolactone (7-α-TS),7-α-thiomethylspironolactone (7-α-TMS), and canrenone(7-α-desthioacetyl-δ-6-spironolactone), may be responsible for itsanti-androgen and anti-stress activities in vivo. In certain aspects,the pharmaceutical compositions may include one or more of thespironolactone metabolites in addition to spironolactone or in place ofspironolactone.

The pharmaceutical composition may be formulated in any form suitablefor the intended method of administration. By way of example, fortopical administration, the composition may be combined with at leastone pharmaceutically acceptable excipient or carrier vehicle in anyconvenient and practical manner, i.e., by solution, suspension,emulsification, admixture, absorption and the like. Such procedures areroutine for those skilled in the art.

In certain embodiments, the pharmaceutically acceptable excipient orcarrier vehicle may be any suitable excipient or vehicle for topical usethat does not interfere with the activity of the spironolactone in anundesired manner. Such excipients and vehicles may include penetrationenhancers, thickeners, solvents, stabilizers, emulsifying agents,buffers, preservatives, etc. Additionally, the composition may includesalts, emollients, antimicrobials, fragrances, etc.

A “penetration enhancer” is an agent known to accelerate the delivery ofthe drug through the skin. These agents also have been referred to asaccelerants, adjuvants, and absorption promoters, and are collectivelyreferred to herein as “enhancers.” This class of agents includes thosewith diverse mechanisms of action including those which have thefunction of improving the solubility and diffusibility of the drug, andthose which improve percutaneous absorption by changing the ability ofthe stratum corneum to retain moisture, softening the skin, improvingthe skin's permeability, acting as penetration assistants orhair-follicle openers or changing the state of the skin such as theboundary layer.

Any suitable penetration enhancer may be used in the context of thepresent disclosure. By way of non-limiting example, penetrationenhancers include functional derivatives of a fatty acid, which includesisosteric modifications of fatty acids or non-acidic derivatives of thecarboxylic functional group of a fatty acid or isosteric modificationsthereof. In one embodiment, the functional derivative of a fatty acid isan unsaturated alkanoic acid in which the COOH group is substituted witha functional derivative thereof, such as alcohols, polyols, amides andsubstituted derivatives thereof. The term “fatty acid” means a fattyacid that has four (4) to twenty-four (24) carbon atoms. Non-limitingexamples of penetration enhancers include C₈-C₂₂ fatty acids such asisostearic acid, octanoic acid, and oleic acid; C₈-C₂₂ fatty alcoholssuch as oleyl alcohol and lauryl alcohol; lower alkyl esters of C₈-C₂₂fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate,and methyllaurate; di(lower)alkyl esters of C₆-C₈ diacids such asdiisopropyl adipate; monoglycerides of C₈-C₂₂ fatty acids such asglyceryl monolaurate; tetrahydrofurfuryl alcohol polyethylene glycolether; polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; alkylaryl ethers ofpolyethylene oxide; polyethylene oxide monomethyl ethers; polyethyleneoxide, dimethyl ethers; dimethyl sulfoxide; glycerol; ethyl acetate;acetoacetic ester; N-alkylpyrrolidone; and terpenes. Other exemplarypenetration enhancers include, but are not limited to, N,N-dimethyllauramide, fatty acids including oleic acid and neodecanoic acid,N-methyl pyrrolidone, etc.

The thickeners used herein may include anionic polymers such aspolyacrylic acid (CARBOPOL® by B.F. Goodrich Specialty Polymers andChemicals Division of Cleveland, Ohio), carboxymethylcellulose and thelike.

Any suitable preservative conveniently added topical formulations may beused, and in such quantities as is taught by the art. For instance,methyl, ethyl, propyl and/or butyl p-hydroxybenzoate may be used insmall amounts, normally not higher than 0.2-0.5 weight percent based onthe total weight of the composition.

Stabilizing agents can be also added to the compositions. Examples ofstabilizers for use in the composition include buffers, pH regulators,antioxidants, amino acids such as glycine and lysine, carbohydrates suchas dextrose, mannose, galactose, fructose, lactose, sucrose, maltose,sorbitol, mannitol, etc.

Additional excipients may generally be found in United StatesPharmacopeia/National Formulary (2000); Remington's The Science andPractice of Pharmacy, Meade Publishing Co. By way of example, theexcipient or carrier vehicle may include a solvent, such as but notlimited to purified water, glycols (e.g., hexylene glycol, propyleneglycol, etc.), alcohols (e.g., ethanol, oleyl alcohol, etc.), propylenecarbonate, mineral oil, and other organic, non-polar solvents.

In certain embodiments, the composition may comprise spironolactone in afoam, lotion, cream or gel carrier vehicle, which may comprise acombination of excipients described herein. By way of example, thecarrier vehicle may contain Versabase™. In certain embodiments, thevehicle may comprise water, ethylhexyl stearate, emulsifying wax,tocopheryl acetate, aloe barbadensis leaf juice, disodiumethylenediaminetetraacetic acid, sorbitol, cyclopentasiloxane,methylchloroisothiazolinone, and methylisothiazolinone.

The actual dosage amount of a composition of the present disclosure maybe determined by physical and physiological factors such as body weight,severity of condition, the type of disease being treated, previous orconcurrent therapeutic interventions, idiopathy of the subject, and onthe route of administration (i.e., topical administration). Dependingupon the dosage and the route of administration, the number ofadministrations of a preferred dosage and/or an effective amount mayvary according to the response of the subject. The practitionerresponsible for administration will, in any event, determine theconcentration of active ingredient(s) in a composition and appropriatedose(s) for the individual subject.

In certain embodiments, pharmaceutical compositions may comprise, forexample, at least about 5% of spironolactone. In other embodiments, thecomposition may comprise between about 5% to about 25.0% spironolactoneby weight of the composition, about 5.1% to about 25% spironolactone byweight of the total composition, about 7.5% to about 25% spironolactoneby weight of the total composition, about 10% to about 25%spironolactone by weight of the total composition, etc. In certainembodiments, the composition may comprise about 5%, about 5.1%, about5.5%, about 7.5%, about 10%, about 15%, about 20%, and any rangederivable therein, spironolactone by weight of the total composition.Naturally, the amount of active compound(s) in each therapeuticallyuseful composition may be prepared in such a way that a suitable dosagewill be obtained in any given unit dose of the compound. Factors such assolubility, bioavailability, biological half-life, route ofadministration, product shelf life, as well as other pharmacologicalconsiderations will be contemplated by one skilled in the art ofpreparing such pharmaceutical formulations, and as such, a variety ofdosages and treatment regimens may be desirable.

Combination Therapy

It is also possible to combine spironolactone with any other topicalagent for use in the treatment or alleviation of a disease, disorder, orcondition related to excess androgen or stress-induced cutaneouschanges, including compounds, in a unitary dosage form, or in separatedosage forms intended for simultaneous or sequential administration to asubject in need of treatment. When administered sequentially, thecombination may be administered in two or more administrations. In analternative embodiment, it is possible to administer one or morecompounds of the present invention and one or more additional activeingredients by different routes.

The skilled artisan will recognize that a variety of active ingredientsmay be administered in combination with the compounds of the presentinvention that may act to augment or synergistically enhance thetreatment or alleviation of a disease, disorder, or condition related toexcess androgen and other hormones.

According to the methods of the invention, the combination of activeingredients may be: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by any other combinationtherapy regimen known in the art. When delivered in alternation therapy,the methods of the invention may comprise administering or deliveringthe active ingredients sequentially, e.g., in separate topicalformulations. In general, during alternation therapy, an effectivedosage of each active ingredient is administered sequentially, i.e.,serially, whereas in simultaneous therapy, effective dosages of two ormore active ingredients are administered together. Various sequences ofintermittent combination therapy may also be used.

To assist in understanding the present invention, the following Examplesare included. The experiments relating to this invention should not, ofcourse, be construed as specifically limiting the invention and suchvariations of the invention, now known or later developed, which wouldbe within the purview of one skilled in the art are considered to fallwithin the scope of the invention as described herein and hereinafterclaimed.

Examples

Topical spironolactone is formulated in a Versabase™ cream carrier, andapplied twice daily directly to affected areas of the cutis. Followingrepeated treatment of a subject in need, the following observations areexpected.

Skin Conditions:

Following one month of treatment with cream applied twice daily toaffected skin areas, a reduction in inflammatory papules, pustules,comedones, cysts, and seborrhea is expected to be observed.

Hair Growth:

Following six months of treatment with the cream applied in the bearddistribution area, a reduction in the number of terminal hairs presentis expected to be observed.

Alopecia:

Following six months of treatment with the foam or solution applied tothe scalp, an increase in the caliber of the hairs is expected to beobserved, thus aiding in treatment of alopecia.

Seborrheic Dermatitis:

Following two months of treatment with cream applied twice daily toaffected areas, a reduction of erythema, pruritus, and rash, in the formof yellow-white greasy flakes, is expected to be observed, thus aidingin the treatment of seborrheic dermatitis.

Overall Outcomes:

Importantly, with all treatments, reduced adverse effects, as comparedto systemic administration is expected. Moreover, a measurable,statistically significant improvement in psychological morbidity andquality of life for subjects is expected. The relationship between theskin and mental health is an intimate one; skin disease is a uniquemalady of the human condition, in that the sufferer must wear thedisease daily in public. Adolescents suffer equally if not more fromdermatologic conditions at a tender time of development; therefore, notaddressing these whole-person concerns can have far-reachingpsychological morbidity.

All publications, patents and patent applications are hereinincorporated by reference to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated by reference.

What is claimed is:
 1. A method for treating or alleviating symptoms ofa disease, disorder, or condition related to excess androgen orstress-induced skin changes in a subject in need thereof, the methodcomprising topically administering a pharmaceutical compositioncomprising about 5% to about 25% spironolactone by weight of the totalcomposition.
 2. The method of claim 1, wherein the pharmaceuticalcomposition comprises from about 15% to about 20% spironolactone byweight of the total composition.
 3. The method of claim 1, wherein thespironolactone is present in an amount effective to affect themicroflora of the pilosebaceous unit.
 4. The method of claim 1, whereinthe disease, disorder, or condition related to excess androgen isselected from patients receiving sex hormone replacements, polycysticovarian syndrome, metabolic syndromes, congenital adrenal hyperplasia,seborrheic dermatitis, or patients experiencing skin senescence andinflammation due to physical and chronic psychological stress states. 5.A method for providing anti-oxidative stress, anti-inflammatory andanti-aging benefits for the skin in a subject in need thereof, themethod comprising topically administering a pharmaceutical compositioncomprising about 5% to about 25% spironolactone by weight of the totalcomposition.
 6. The method of claim 5, wherein the pharmaceuticalcomposition comprises from about 15% to about 20% spironolactone byweight of the total composition.
 7. The method of claim 5, wherein thesubject is suffering from UV radiation, systemic chemotherapy, or othersystemic physiological stress states that induce oxidative stress on theskin of the subject.